Major recent advances in the clinical management of prostate cancer and in the molecular technologies available to dissect the action of the androgen receptor (AR) are re-shaping therapeutic goals, and new methods of monitoring patient hormonal status and response are needed. Rational design of new strategies for prostate cancer hormonal therapy and effective monitoring of patient response to hormonal manipulation is a priority area for clinical research, and one that is inadequately supported by current technologies. The major objective of the project described in this proposal is the design and fabrication of a battery of micro-scale yeast based bioassays or "biochips" that can be used to monitor AR ligands in sera and tissue extracts from patients with prostate cancer. Conceptually, this clinical application of yeast AR biochip technology is similar to the use of conventionally formatted yeast based assays in toxicological screens to detect environmental endocrine disrupters (or endocrine active compounds). However, the use of yeast based bioassays for steroid receptor ligands in a clinical environment is currently limited by the availability of human expertise and labor, the cost of reagents and the amount of biological sample. The MIT Bio-Instrumentation Lab (Professor Hunter's group) is currently actively engaged in the development of living chips, microdevices which use arrays of living cells for massively parallel detection of biochemical and biophysical events, including a two-dimensional microchannel array technology specifically for yeast-based assays used in drug discovery. In this grant we propose to adapt this technology for a particular clinical application: the automated screening of sera and tissue extracts for biologically active AR ligands. Specifically, we will use this new assay technology to measure changes in AR ligand profiles in prostate cancer patients as a function of clinical history, therapy, and changes in established indices of disease status. With the successful fabrication and validation of these yeast AR biochips, it will be possible to monitor one of the major biological determinants of prostate cancer progression - the bioavailable levels of androgen and other AR ligands - in a timely, cost effective manner.